2alpha-methyl-delta3-androstene-17-hydrocarbon derivatives



A -androstene derivatives.

United States Patent Ofiflce Patented Dec. 29, 1964 3,163,663 2u-METHYL-A -ANDRSTENE-17-HYDR0- CARBON DERIVATIVES Alexander D. Cross and Albert Bowers, Mexico City, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama N0 Drawing. v Filed Dec. 4, 1961, Ser. No. 156,984

7.Claims. (Cl. 260-3975) The presentinvention relates'to novel cyclopentano phenanthrene compounds and to a process for the produc- In the above formulas R may be hydrogen or methyl; R represents hydrogen or a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R may be hydrogen or an alkyl, alkenyl or alkynyl group of up to 6 carbon atoms.

The novel compounds of the present invention are prepared by the process exemplified by the following equation: 1 v i In the above formulas R and R have the same meaning as previously described. In practicing the process outlined above one of the star-ting compounds which is testosterone (I) is treated with hydrazine hydrate and the formed hydra'zone is decomposed by heat preferably in ethylene glycol at reflux temperature, thus yielding the corresponding A -androsten- 175-01 derivative (IV; R=H).

Following a second sequence of reactions the'starting material, Za-methyl-4a-bromo-testosterone (II) is reduced preferably with sodium borohydride yielding Zea-methyl- 4a-bromo-androstane-3fi,17fi-diol (III) which upon treatment with a suitable reagent such as zinc in acetic acid at approximately 90 C. for a period of time of the order of 1 hour yields the corresponding 2a-methyl-A -andr0- sten-17/3-ol (IV; R=CH The A -androsten-17/3-o1 derivative (IV) is oxidized, preferably with chromium trioxide in pyridine, .thus affording the corresponding 17-ketone (V). Treatment of this compound with an alkyl, alkenyl or alkynyl magnesium halide as for example methyl, vinyl or ethynyl magnesium bromide, yields the corresponding 17o alkyl, alkenyl or alkynyl-lm-o-l derivative (VI).

The compounds of the present invention represented by the Formula IV are conventionailyacylated in pyridine with an acyla-t-ing agent, as for example acetic anhydride, afiording the corresponding l7-acy1ate, The compounds represented by Formula (VI), are conventionally acylated in the presence of p-toluenesulfonic acid, with an 'acylating agent, as for example an anhydride of a a hydrocarbon carboxylic acid of the type described hereinbefore, to give the corresponding 17-acylates.

The following specific examples serve to illustrate but are notintended to limit the scope of the present invention:

Example I A mixture of 1 g. of testosterone, 2 g. of hydrazine hydrate, 1.2 g. of potassium hydroxide, 1.2 cc. of'water and 1.2 cc. of diethylene glycol was heated under reflux for 45 minutes. It was then heatedin aln open flask until the temperature of the reaction mixture reached 200 C.,' a reflux condenser was attached, and refluxing was continued for a further ,2 hours. The solution :was cooled,

water added and the product isolated by extraction with ether. Recrystallization of the residue obtained .wafter evaporation of the solventfrom acetone-hexane afforded A -andr0sten-17B-ol.

' Example ll Asolution of l g. of sodium borohydride in 3 cc. of

water was added to an ice-cooled solution of l g. of 2a-methyl-4a-bromo-androst-am17fi-ol-3-one. [Mauli et aL, J.A.C. S. 82, 5494 (19 60)] in cc. of methanol" and the mixture was allowed to stand for 16 hours at room temperature. The excess reagentwas decomposed by addition at acetic acid, thesolntion concentrated to small volume invacuo and-diluted with; water. The" product was extracted with ethyl acetate, the extract was washed with water, dried-and evaporated. The solid residue was purified by crystallization from acetone-hexane to give 2a-methyl-4a-bromo-androstane-3p,17 8-diol.

Example III Several batches of the foregoing compound adding up to 7 g. were mixed with 7 g, of zinc dust in 150 cc. of glacial acetic acid and kept at 90 C. for 1 hour at the end of which the mixture was filtered through celite. The filtrate-was concentrated to a small volume under reduced pressure, cooled and diluted with ice water to precipitate a crude product. Recrystallization from acetone-hexane afforded 2a-methyl-A -androsten-17,8-01.

Example 'IV" A solution of 6 g. of A -androsten-17/3-o1 (obtained in accordance with Example I), in 120 cc. of pyridine, was added to a mixture of 6 g. of chromic trioxide in 120 cc. of pyridine. The reaction mixture was kept at room temperature overnight. It was then diluted with ethyl acetate, filtered through celite and the filtrate washed well with water, dried and evaporated to dryness. Crystallization from acetone-hexane aiforded A -androstene-17- one.

2a methyl A -androsten-17fi-ol was treated by the above procedure yielding 2a-methyl-A -androsten-17-one.

Example V A solution of g. of A -androsten-17-one in 250 cc. of thiophene-free benzene was treated with 27.5 cc. of 4 N methyl magnesium bromide in ether and the mixture refluxed with the exclusion of moisture for 3 hours. The cooled mixture was cautiously treated with excess aqueous ammonium chloride solution and the product isolated by ethyl acetate extraction. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness.

Recrystallization from methylene chloride-hexane afforded 17a-methyl-A -androsten-1718-01.

2a methyl A -androsten-17-one was treated by the above method furnishing 2a,17a-dimethyl-A -androsten- 175-01.

Example VI Using exactly the same conditions described in Example V but substituting methyl magnesium bromide by vinyl magnesium bromide, there were treated A -androsten-l7-one and 2a-methyl-A -androsten-17-one yielding respectively 17u-vinyl-A -androsten-175-01 and Zea-methyl-17a-vinyl-A -androsten- 17 (3-01.

Example VII A -androsten-l7-one and 2a methyl-A3-androsten-17- one were treated following the technique described in EX- ample V except that methyl magnesium bromide was substituted by ethynyl magnesium bromide, thus furnishing 17a-ethynyl-A -androsten-l7B-ol and 2a methyl-17a-ethynyl-A androsten-17p-ol.

I Example VIII A mixture of 1 g. of A -androsten-17fi-ol, 4 cc. of pyridene and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave A -androsten-17 8-o1- 1 acetate.

Using exactly the same conditions described above,

there was treated 2a-methyl-A -androsten-175-01, thus giving 2a-methyl-A -androsten-17p-ol-acetate.

Example IX A -androsten-l7B-ol and 2a-methyl-A -androsten-l7,8-01 were treated following the technique described in Exam ple VIII except that acetic anhydride was substituted by propionic anhydride, affording correspondingly A -androsten-l7p-ol-propionate and ,2a-me'thyl-A -androsten-17,8- o1-p'ropionate.-.

4 Example X Using the same conditions described in Example VIII but substituting acetic anhydride by caproic anhydride. there were obtained A -androsten-17 3-ol caproate and 2amethy1-A -androsten-17p-o1 caproate.

Example XI Following the procedure described in Example VIII except that acetic anhydride was substituted by benzoyl chloride, there were obtained A -androsten-17B-ol-benzo ate and 2a-methyl-A -androsten-l7p-o1 benzoate.

Example XII A mixture of 1 g. of 17a-methyl-A -androsten--01, l g. of p-toluenesulfonic acid monohydrate, 50 cc. of acetic acid and 25 cc. of acetic anhydride was kept for 24 hours at room temperature. It was-then poured into water and stirred until the excess of anhydride'had hydrolyzed. Isolation of the product by methylene chloride, extraction and crystallization of the residue from acetone-ether gave the l7-acetate of l7a-methyl-A -androsten-17fl-ol.

By the above procedure, there were treated the starting compounds listed below, furnishing the hereinafter disclosed products:

Starting compounds Products 20:, 17a-dimethyl-A -audr0sten- 17-acetate of 2a, 17a-dimethyl-M- 2a-rnethy1-17a-viny1-A androstenl7-acetate ot2a-methy1-17a-viny1- 718-01. A -androsten-flfl'ol.

2a-methy1-17aethyny1-A 17-acetate of 2a-mothyl-l7uandrosten-UB-ol. ethynyl-A -and.rosten-17fl-o1. 17a-viny1-A -andr0sten-17fi-ol l7aceigltse (11f 17a-viny1-A -androsen- -0 17a-ethyny1-A -andr0sten-l7fi-o1 17-acetate of l7a-ethyny1-A androsten-UB-ol.

Example XIII wherein R is a member of thegroup consisting of lower alkyl, lower alkenyl and lower alkynyl and R is selected from the groupconsisting of hydrogen anda hydrocarbon carboxylic acid of less than twelve carbon atoms.

(References on following page) 5 6 References Cited by the Examiner De Winter at 211.: Chemistry and Industry, 1959, page UNITED STATES PATENTS 7 .1 a 5 I 2 3,055,916 9/ 2 Bowers 611211. 260397.3 t al I CS (London) 19 9 Pages 502 3064014 11/62 Jongh et 260 397"5 5 Nomine et aL': Compt. Rend. Akad. Sci. vol. 252, NO.

OTHER REFERENCES 25, June 1961, pages 3903-3905.

Fieser and Fieser: Steriods, Reinhold Publishing Col-6., LEWIS GOTTS p'limary Examiner 1959, page 476. IRVING MARCUS, Examiner. 

7. A COMPOUND OF THE FOLLOWING FORMULA: 